Coenzyme Q is an essential constituent widely distributed in living bodies, from bacteria to mammals and is known as a mitochondrial electron transfer system constituent in cells of living bodies. Through repeated oxidation and reduction in mitochondria, coenzymes Q perform their function as transmitter components in the electron transfer system and, further, reduced coenzymes Q are known to have antioxidant activity. In humans, coenzyme Q10, whose coenzyme Q side chain comprises 10 repeating structures, is the main component and, generally, about 40 to 90% thereof is present in reduced form in living bodies. The physiological activities of coenzyme Q involve the activation of energy production through mitochondrial activation, activation of cardiac function, stabilizing effect of cell membrane, cell protecting effect through antioxidant activity, and the like.
Oxidized coenzyme Q10 is used as a health food in the United States and Europe, and as a medication for congestive heart failure in Japan. In recent years, it has come to be used in Japan as a functional nutritive food. Soft capsules containing oxidized coenzyme Q10 predominate especially in the field of health foods and functional nutritive foods.
On the other hand, since reduced coenzyme Q itself has strong antioxidant action, it is possible to effectively increase the antioxidant activity in blood by supplying sufficient quantities of reduced coenzyme Q to blood. Increasing the antioxidant activity in blood is thought to have a wide range of usefulness for many diseases from being aggravated supposedly by active oxygen species, for example, preventing vascular lesions during ischemia-reperfusion, preventing restenosis in arteriosclerosis, preventing vascular lesions following cerebral infarction, preventing arteriosclerosis, preventing complications of diabetes.
It is known that reduced coenzyme Q10 can be obtained, for example, by well-known conventional processes such as synthesis, fermentation, extraction from natural sources, and the like, and then concentrating the reduced coenzyme Q10 fraction of the effluent resulting from chromatography (Japanese Kokai Publication Hei-10-109933). In this case, as described in the above-cited publication, the chromatographic concentration may be carried out after reduction of oxidized coenzyme Q10 contained in the reduced coenzyme Q10 with a conventional reducing agent such as sodium borohydride or sodium dithionite, or reduced coenzyme Q10 may be prepared by reacting an existing highly pure grade of coenzyme Q10 with the reducing agent mentioned above.
Moreover, as a result of intensive research, the present inventors established processes for producing high-quality reduced coenzyme Q10, which were disclosed in patent applications (WO03/06408; WO03/06409; WO03/06410; WO03/06411; WO03/06412; WO03/08363; and WO03/32967).
However, reduced coenzyme Q10 is readily oxidized to oxidized coenzyme Q10 by molecular oxygen, and, even when a high-quality reduced coenzyme Q10 is manufactured by a method like the above-mentioned patent applications, it is still an important problem to stabilize reduced coenzyme Q10 in processing the same in foods, functional nutritive foods, specific health foods, nutritional supplements, nutrients, animal drugs, drinks, feeds, cosmetics, medicines, remedies, preventive drugs, etc., or raw materials or compositions for the production thereof, and/or to stabilize the same in preserving such products, raw materials or compositions after processing the same. On the occasion of such process and preservation, it is very difficult to completely eliminate or shut out oxygen and, in particular in the step of warming for processing or during long-period preservation of them, the remaining or newcomer oxygen exerts a great adverse influence. This oxidation is directly concerned with such quality problems as the formation of oxidized coenzyme Q10 as a byproduct.
Thus, it is a very important problem to stabilize (protect against oxidation) reduced coenzyme Q10. To this time, however, few studies have been made on the method and composition for stabilizing coenzyme Q10. There are only two examples; one describes a composition comprising a coexisting reducing agent and a method for producing the same (WO01/052822) and, in the other, reduced coenzyme Q10 is stabilized in an oil or fat (WO03/062182).
In WO01/052822, there are disclosed 1) a composition comprising an amount, effective in preventing reduced coenzyme Q10 from being oxidized to oxidized coenzyme Q10, of a reducing agent and an amount, effective in dissolving the reduced coenzyme Q10 and reducing agent, of a surfactant or a vegetable oil or a mixture of these, if necessary together with a solvent, 2) a composition for oral administration in the form of gelatin capsule or tablets as prepared from the above composition and, further, 3) a method for preparing the above composition containing reduced coenzyme Q10 in situ by using oxidized coenzyme Q10 and a reducing agent.
In WO01/052822, however, there is no detailed description of the quality and the stabilizing effect of the reduced coenzyme Q10 contained in the above-mentioned compositions, for example. The above-mentioned compositions and the method for preparing the same are very complicated and troublesome so that the compositions may play a plurality of roles (namely the first role as a reaction field for the reduction of oxidized coenzyme Q10 to reduced coenzyme Q10 and the second role in maintaining reduced coenzyme Q10 in a stable condition).
Furthermore, it is noteworthy that the above compositions and/or the method for preparing the same are hard to be referred to as always safe since the reaction mixture is used as such. More specifically, the use of ascorbic acids as a reducing agent in reducing oxidized coenzyme Q10 to reduced coenzyme Q10 results in the oxidation of the ascorbic acids, leading to the formation of a considerable amount of the corresponding dehydroascorbic acids, which contaminates the above-mentioned compositions. Unlike ascorbic acids, dehydroascorbic acids and the decomposition product oxalic acid are highly harmful. For example, they reportedly cause increases in lipid peroxide level and decreases in antioxidant level in the liver and kidney and increases in oxalic acid level in the kidney, and there is a fear of their producing some adverse effects, for example the effects of decreasing the resistance to oxidative stress and readily causing ureterolithiasis (Nutrition Research, 13, pp 667-676(1993)).
Furthermore, although ascorbic acids are used in W001/052822, when ascorbic acids are enclosed in a gelatin soft capsule, it is generally known that the disintegration of the gelatin capsule will get worse. Therefore, there is also fear that the absorbability to a living body will be adversely affected in this case.
In WO03/062182, on the other hand, a method for stabilizing reduced coenzyme Q10 which is characterized in that reduced coenzyme Q10 is admixed in a composition whose main components are oils and fats (except for olive oil) and/or a polyol and which will not substantially interfere with the stabilization of reduced coenzyme Q10 is disclosed as a method for protecting reduced coenzyme Q10 against oxidation. However, in the above stabilization method, reduced coenzyme Q10 could not be preserved stably, for example in the case of being incorporated with sorbitan fatty acid esters and/or polyoxyethylenesorbitan fatty acid esters, because of limitation of materials which could be used.
A method which can preserve reduced coenzyme Q10 stably has been searched for under the above situations.